I would like to present to you a novel and truly unusual hypothesis about the origin of aging and aging-related medical phenomena, including Alzheimer's disease.
To get a first impression of the hypothesis, it is sufficient to read part 1, = 800 words.
TL;DR: An extremely weak, but extremely often activated self-reference mechanism in the memory system creates about 1 billion extremely weak memories of a special type in the course of life. Their combined, slowly increasing inhibitory effects on cellular repair mechanisms, meditated by so-called brain-body mechanisms, create the aging process and associated diseases.
PART 1: THE HYPOTHESIS
The hypothesis is based on the following 4 premises:
1 A memory trace, once formed in the neuronal networks of the brain, is never fully inactive. Rather it is permanently active to a tiny extent (let’s say around a micro-percent) compared to its activity during memory recall. The mechanisms causing this phenomenon are:
Existing memory traces are constantly slightly activated by both incoming and intrinsic neuronal activities that take place within memory systems (see e.g. Pubmed-Ids: 18319728 and 10980021).
In particular, aversive memories tend to lose small proportions of their inhibitory control over time, leading to their slight, permanent overactivity (more details below).
I call this tiny basic activity of a memory trace generated by the above mechanisms the “OVEREXPRESSION” of a memory.
2 The overexpression of an aversive memory, e.g. a pain memory, has an extremely weak, anti-homeostatic effect on body and brain.
This follows from research results of Brain-Body medicine, which investigates the influence of emotions on physical health.
The basic argument underlying this claim is that if a negative emotion has a proven anti-homeostatic effect, then the overexpressed memory of that emotion will have the same effect, only much weaker (see e.g. Pubmed-Id: 19524045; more follows also below).
3 Now the completely crazy part: The normal memory perception mechanisms that exist in all animals with nervous system, lead to the unconscious perception of the OVEREXPRESSED EMOTIONAL COMPONENTS of aversive memories ...
... AND TO THE CONTINUOUS AND UNCONSCIOUS RE-MEMORIZATION of these overexpressed emotional components as part of the emotionality of the normal, ongoing autobiographical events ... followed by their RE-OVEREXPRESSION, ... and subsequent re-memorization ... and so on ... moment by moment, the whole life long.
Ok, that sounds really weird. Therefore again step by step:
Step 1: All memories of aversive events of your life are permanently a little bit active (i.e., „overexpressed“), thereby slightly shifting your state of mood towards negativity.
Step 2: This (consciously imperceptible) slightly negative state of mood is re-memorized as an aversive emotional memory along with the current autobiographical event. As this newly formed memory is also overexpressed, this step increases the number of aversive memories that are overexpressed.
Step 3: The now increased number of overexpressed aversive memories in turn increases to a tiny extent the negativity of your state of mood, which is again re-memorized as in step 2 ... and so on, moment by moment, the whole life long.
In this way, the number of aversive memories that are overexpressed, and likewise their combined anti-homeostatic effect (remember point 2 above), increases constantly in an unstoppable manner. This is obviously a vicious cycle (hereafter just called “VC”). Vicious, because it induces a steadily increasing anti-homeostatic effect in the body, which may react with potentially dangerous health problems (see below).
Since a new autobiographical event is generated and memorized roughly every second (actually when a new visual scene occurs after an eye movement), overexpressed memories are re-memorized also roughly every second. The VC creates therefore during a human life about one BILLION of very, very, very slightly aversive memories - and every single one of them exerts a very, very, very slight anti-homeostatic effect on the body.
(Yes, you read that right, one BILLION, 10 ^ 9, 1000 MILLIONS of memories ... no joke.)
A side note: It sounds a bit ridiculous, but the VC basically works like the mechanism „compound interest with contributions” in the financial sector. It starts as soon as the first aversive memory has been formed. Aversive memories, which are subsequently formed by negative life experiences, are "contributions". And like compound interest, the VC has enormous effects over a longer period of time.
Another side note: Since the future relevance of aversive memories can not be predicted, they remain memorized for a lifetime and never completely decay (proved in animal experiments; in humans, traumatic memories are an example for the long lifetime of aversive memories). Therefore, the VC really creates the postulated high number of aversive memories. But many of them lose a lot of their contextual information throughout life. For background information, google „silent engram“.
4 Now the last and decisive statement of the hypothesis:
THE COMBINED ANTI-HOMEOSTATIC EFFECTS OF THE VERY, VERY, VERY SLIGHT OVEREXPRESSION OF ALL THE MEMORIES FORMED BY THE VC, CREATE IN THE LONG RUN, MAINLY BY INHIBITING CELLULAR REPAIR AND REJUVENATION MECHANISMS, THE AGING PHENOTYPE AND RELATED DISEASES.
(To keep you on the hook, I'd like to reveal that a gene expression study indeed suggests that the most important brain area of human memory, the hippocampus, actually causes a cascade of physical aging in some tissue. In addition, there is a study showing that the skin of mice is AUTOMATICALLY REJUVENATED as soon as a particular pro-inflammatory molecule is blocked whose activity is driven by the VC. More below ...)
PART 2: EXACT MECHANISMS AND IMPORTANT PROPERTIES OF THE VC
Short note: for the sake of brevity, instead of using the complicated phrase:
"the overexpression of the aversive memories created by the VC induce effect X ...",
I will use in the following the phrase:
"the VC-memories induce effect X ...",
or even more simply, "the VC induces effect X ...".
HOW DOES THE VC INHIBIT REPAIR MECHANISMS?
Before I go into the exact mechanisms by which the VC inhibits repair mechanisms and thereby eventually creates the aging phenotype, let me first explain how the VC generally activates physiological mechanisms.
According to my hypothesis, as briefly explained in point 2, the VC-memories generate their anti-homeostatic effect by triggering a series of brain-body mechanisms.
As also briefly explained in point 2, the basic argument behind this assertion is that if a negative emotion has a proven negative physiological effect, then the overexpressed memory of that emotion has the same physiological effect, only weaker.
The following quotes from a fundamental review article of brain-body medicine support this argument:
First of all, the following quote briefly summarizes the data situation that motivates an independent brain-body medicine:
“... what this juxtaposition [of scientific papers] reveals is that there is a remarkable commonality of brain areas and brain mechanisms that appear again and again in these [brain-body neuroimaging] papers. This commonality, which exceeded our expectations, suggests that there is a coherent field of neurobiology that relates emotion, emotion regulation and stress on the one hand to systemic medical disorders and peripheral physiological processes on the other.” (Lane and Wager, 2009, p. 1135)
The next quote demonstrates the harmful physiological effects of negative emotions:
„the field of Brain–Body Medicine has ... unequivocally demonstrated that negative emotional states such as depression and stress have deleterious effects on physical health“ (Lane and Wager, 2009, p. 1135)
The following decisive quote demonstrates the negative physiological effect of continuously active brain-body mechanisms triggered by negative emotions or permanent negative emotional states.
„Since these [brain-body] mechanisms related to [negative] emotion are in continuous operation, their integrated influences across months or years are likely to have clinically important effects on disease processes and outcome. Indeed, that is what the epidemiological evidence indicates ...“ (Lane and Wager, 2009, p. 1135)
The important conclusion now is:
SINCE THE MEMORIES GENERATED BY THE VC ARE PERMANENTLY, 24/7, OVEREXPRESSED AND CONTINUOUSLY TRIGGER THE CORRESPONDING DELETERIOUS BRAIN-BODY MECHANISMS, THEY EXERT A SIGNIFICANT NEGATIVE PHYSIOLOGICAL EFFECT, SIMILAR TO THE EFFECT POSTULATED IN THE ABOVE QUOTE BY LANE AND WAGER FOR NEGATIVE-EMOTION RELATED BRAIN-BODY MECHANISMS THAT ARE IN CONTINUOUS OPERATION.
This, in turn, leads directly to the conclusion that the VC can trigger all diseases which, according to brain-body medicine, can be triggered by negative emotions: cardiovascular diseases, high blood pressure, chronic pain, etc.
(Please note here that the validity of this conclusion depends only on quantitative factors, since the phenomenon of overexpression of memories, as well as the resulting effects on brain-body mechanisms, certainly exists to some extent. The only question is whether the phenomenon of memory overexpression is strong enough to exert a significant activating influence on brain-body mechanisms.)
These were the explanations on how the VC generally triggers brain-body mechanisms. In order to substantiate that the VC produces the aging phenotype, it remains to be shown that among the brain-body mechanisms activated by aversive memories there are also those that inhibit repair mechanisms. In this case, the VC would generate the characteristics of the aging phenotype, such as accumulation of cell and tissue damage and molecular waste products, by inhibiting repair mechanisms.
The available literature on brain-body mechanisms shows that the VC achieves the postulated inhibitory effect on repair mechanisms mainly because overexpressed aversive memories activate brain-body mechanisms that deregulate the neuroimmunoendocrine system (i.e., ANS, immune, and endocrine systems).
The main result of this deregulation (examples follow below) is a tendential shift of cellular mechanism from anabolic to catabolic. This shift inhibits repair mechanisms, including stem cell activity necessary for tissue regeneration.
The main conclusion of my hypothesis is therefore that the inhibitory effect of the VC on repair mechanisms, acting over decades, eventually leads to the accumulation of molecular waste products and cell and tissue damage, thereby allowing the onset of the aging phenotype. This means that the VC is not directly but causally responsible for the aging process.
As an example, I would like to describe here one brain-body mechanism that is triggered by aversive memories and actually gives the VC an inhibitory effect on repair mechanisms.
According to brain-body medicine aversive experiences trigger the release of stress hormones:
—> It follows that overexpressed memories of aversive experiences lead in the same way to the release of stress hormones.
—> This also applies to the aversive memories generated by the VC.
—> Since VC-memories are continuously overexpressed, this means that the VC triggers a continuous release of stress hormones. (And, indeed, the level of stress hormones in the blood increases steadily as you get older.)
—> Since stress hormones have a catabolic effect (see e.g., PMID 6365973, or Wikipedia on „Catabolism“), it follows that the VC has a permanent catabolic effect and therefore permanently inhibits cellular repair mechanisms. Q.E.D.
Since the results of brain-body medicine are very extensive and include a variety of brain-body mechanisms, further mechanisms that give the VC inhibitory effects on repair mechanisms can easily be derived. An example of how the VC inhibits repair mechanisms by means of the autonomous nervous system follows below.
To better understand the central importance, scope, and detail of brain-body medicine, I strongly recommend reading the abstracts and introductions to the following review articles:
What are the „unique selling points“ of the VC hypothesis?
None of the approximately 300 aging theories can explain all aspects of the aging process. The main problem of many of these theories is the lack of a clear cause-effect relationship between the aging process and its postulated origin. For example, in the free radical aging theory it is by no means clear whether the formation of free radicals leads to the aging process or is an effect of it. The same applies to all damage theories of aging (DNA damage theory, AGEs theory, protein damage theory, etc.).
In the VC hypothesis, however, the cause-effect relationship is unambiguous. The causality chain leading to the aging process begins with the formation of aversive memories and ends at the molecular endpoints of the brain-body mechanisms triggered by aversive memories.
The reason this mechanism has so far been overlooked is that among the multitude of molecular changes (ROS, AGEs, DNA damage, etc.) triggered by VC in the body, there is no unambiguous evidence that clearly points to the memory system as the origin of all these changes. The causality chains leading to these changes are simply too long, too diverse and too spatially separated to be recognized solely by the molecular changes at the endpoints of the causality chains.
Another important unique selling point of the VC hypothesis is its ability to explain, as the only one among the aging theories, certain experimental interventions leading to automatic tissue rejuvenation. This point is discussed in more detail below.
CONSEQUENCES OF AN AMPLIFIED VICIOUS CYCLE
Part 1 of this text described the VC, how it is running in its normal velocity in all animals with nervous system.
In this „normal“ velocity, the VC has after my hypothesis already a strong deleterious effect and causes or promotes in humans, mainly through its pro-inflammatory action, all the major aging-related diseases: cancer, type 2 diabetes, cardiovascular disease, etc.
This is already bad news. But unfortunately, since the VC has several intrinsic positive feedback loops, various influences are able to shift the VC into an amplified state, where it has an even stronger disease inducing effect.
In this amplified state, it creates significantly stronger aversive memories, ranging in number from dozens to hundreds of millions, depending on when in life the amplifying event took place.
The consequences of an amplified VC are disastrous in several ways:
All aging-related diseases may occur up to decades earlier.
Existing health problems of any kind, occurring at any age, are amplified by the significant anti-homeostatic effect of an amplified VC.
A whole range of new health problems specific to an amplified VC may occur (see the second part of the Introduction page on my website).
INITIATING EVENTS
The major initiating events that lead to an amplified VC are:
The formation of traumatic memories. Its overexpression and re-memorization significantly increases the strength of memories created by the VC, and, consequently, their anti-homeostatic effects.
The induction of a chronic, subclinical brain inflammation due to various factors, like strong infections, concussion, toxic events, etc. This amplifies the VC in two, quite astonishing, ways:
A) The cytokines released during a brain inflammation induce a subclinical „sickness behavior” (see google), which entails a slightly aversive state of mood. This reinforces the VC, since from now on the memories generated by the VC are slightly more aversive.
B) Brain inflammation indirectly disinhibits aversive memories by increasing the cell-death rate among a special type of very stress-sensitive neurons that control aversive memories (the so-called „PV+ interneurons“, see more on my website, or google “Interneuron Energy Hypothesis” and PMID 24256726). This leads to an increased overexpression of the affected aversive memories, which in turn reinforces the VC.
The process B is, in my hypothesis, also to a certain extent induced by normal brain aging, and therefore represents the second general mechanism — besides the persistent neuronal activity in memory systems mentioned in premise 1 — which leads to memory overexpression.
Influences that take advantage of this second mechanism of memory overexpression are in my opinion the most important and most dangerous entry points into an amplified VC.
Furthermore, aversive memories, especially traumatic ones, most probably promote brain inflammation (as their overexpression triggers mild stress, which in turn promotes brain inflammation, see PMID 23537508). This would additionally reinforce the VC by inducing two further positive feedback loops into the VC via the two mechanisms A and B described in the preceding paragraphs.
THE VICIOUS CYCLE MUST BE DISTINGUISHED FROM CLASSICAL DISEASE MECHANISMS
The VC is basically a natural process that slowly drives many biological regulatory systems in body and brain out of their state of equilibrium. This implies several specific properties for the VC that distinguish it from classical disease mechanisms:
THE VC-INDUCED DISEASES HAVE A COMMON ORIGIN. BUT THEY NEVERTHELESS APPEAR TO BE COMPLETELY DIFFERENT MEDICAL PHENOMENA BECAUSE EVERY BIOLOGICAL REGULATORY MECHANISM DEREGULATED BY THE VC, PRODUCES ITS OWN COMPLEX OF SYMPTOMS.
IT IS DIFFICULT TO PREDICT WHICH DISEASES THE VC WILL CREATE IN AN INDIVIDUUM, BECAUSE THE WAY THE VC DEREGULATES BIOLOGICAL REGULATORY MECHANISMS DEPENDS IN AN EXTREMELY COMPLEX WAY ON GENETICS, EARLY LIFE EPIGENETIC PRIMING, LIFESTYLE, AND AUTOBIOGRAPHICAL MEMORY CONTENT.
SINCE THE VC GENERALLY DEREGULATES NOT ONE, BUT SEVERAL BIOLOGICAL REGULATORY MECHANISM, THE VC-INDUCED DISEASES HAVE A HIGH CO-MORBIDITY.
The main similarities of the VC-induced diseases are:
They are driven by chronic inflammation (since the main detrimental effect caused by the VC is chronic inflammation in brain and body, and chronic inflammation has multiple tissue-damaging effects).
Their main risk factor is aging (since in general, the VC's anti-homeostatic effects take decades to rise to a disease-inducing level).
The hypothesis is supported by the following research findings:
GENE EXPRESSION ANALYZES SUGGEST AN IMPORTANT HUMAN MEMORY SYSTEM TO CAUSE AGING IN SOME TISSUE
A 2011 study of Huang et al. about aging-related gene expression in various tissues (https://www.ncbi.nlm.nih.gov/m/pubmed/21751870/), concludes that „the aging of hippocampus caused some kind of cascade of aging in other tissue“.
The hippocampus is the area of the brain responsible for autobiographical memory. The hippocampus is also known for its decisive role in inhibiting aversive memories. Damage to the hippocampus would, therefore, disinhibit aversive memories.
The (after my hypothesis) thereby resulting brain-wide increased level of inflammation would in turn predominantly damage the hippocampus, because it is one of the most sensitive structures of the brain. This would further disinhibit aversive memories, and so on, and so on.
This means that the hippocampus could be an area of the brain that is simultaneously the origin and target of one of the mechanisms that form and amplify the VC.
This possible role of the hippocampus as a major source and target of the VC, and therefore as a major causal source of an aging-promoting influence on the body, could be the reason why Huang et al., 2011 found the hippocampus as the causal source of the aging-related gene expression changes in some tissues of the body.
MICE SKIN AUTOMATICALLY REJUVENATES WHEN BLOCKING A MOLECULAR MECHANISM WHICH IS DRIVEN BY THE VC
My hypothesis postulates that the VC creates aging in all animals with nervous system by inhibiting repair and rejuvenation mechanisms (for exact mechanisms, see my website). Interestingly, a study shows that a molecular mechanism (the pro-inflammatory activity of the NF-κB molecule), actually exists in the skin of mice, that
a) becomes more and more active as the mice grow older, and
b) THE BLOCKING OF WHICH LEADS TO AUTOMATIC SKIN REJUVENATION.
This, in fact, suggests that aging, as postulated by my hypothesis, arises from inhibiting of repair and rejuvenation mechanisms. In this case, the inhibiting of repair and rejuvenation mechanisms is due to the overactivity of NF-κB (for details see PMID 18055696).
In addition, because the VC is highly pro-inflammatory and therefore strongly potentiates the activity of NF-κB (see e.g. PMID 19408108), the VC might be responsible for the aging-related increased activity of NF-κB and, thus, also for the resulting skin aging through the NF-κB-induced inhibition of repair mechanisms. The VC could therefore indeed represent the origin of the skin-aging process in mice.
A CAUSAL CHAIN FROM THE VC, TO THE AUTONOMOUS NERVOUS SYSTEM, TO AGING
A research line (see PMIDs (29932493 and 30303708) found, that a major source of tissue aging, the decline of stem cell proliferation during growing older, is caused (at least in vitro) by an imbalance in the activity of the two..
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